Experimentally generated randomness certified by the impossibility of superluminal signals.

From dice to modern electronic circuits, there have been many attempts to build better devices to generate random numbers. Randomness is fundamental to security and cryptographic systems and to safeguarding privacy. A key challenge with random-number generators is that it is hard to ensure that their outputs are unpredictable1-3. For a random-number generator based on a physical process, such as a noisy classical system or an elementary quantum measurement, a detailed model that describes the underlying physics is necessary to assert unpredictability. Imperfections in the model compromise the integrity of the device. However, it is possible to exploit the phenomenon of quantum non-locality with a loophole-free Bell test to build a random-number generator that can produce output that is unpredictable to any adversary that is limited only by general physical principles, such as special relativity1-11. With recent technological developments, it is now possible to carry out such a loophole-free Bell test12-14,22. Here we present certified randomness obtained from a photonic Bell experiment and extract 1,024 random bits that are uniformly distributed to within 10-12. These random bits could not have been predicted according to any physical theory that prohibits faster-than-light (superluminal) signalling and that allows independent measurement choices. To certify and quantify the randomness, we describe a protocol that is optimized for devices that are characterized by a low per-trial violation of Bell inequalities. Future random-number generators based on loophole-free Bell tests may have a role in increasing the security and trust of our cryptographic systems and infrastructure.

Device-independent quantum random-number generation.

Randomness is important for many information processing applications, including numerical modelling and cryptography1,2. Device-independent quantum random-number generation (DIQRNG)3,4 based on the loophole-free violation of a Bell inequality produces genuine, unpredictable randomness without requiring any assumptions about the inner workings of the devices, and is therefore an ultimate goal in the field of quantum information science5-7. Previously reported experimental demonstrations of DIQRNG8,9 were not provably secure against the most general adversaries or did not close the 'locality' loophole of the Bell test. Here we present DIQRNG that is secure against quantum and classical adversaries10-12. We use state-of-the-art quantum optical technology to create, modulate and detect entangled photon pairs, achieving an efficiency of more than 78 per cent from creation to detection at a distance of about 200 metres that greatly exceeds the threshold for closing the 'detection' loophole of the Bell test. By independently and randomly choosing the base settings for measuring the entangled photon pairs and by ensuring space-like separation between the measurement events, we also satisfy the no-signalling condition and close the 'locality' loophole of the Bell test, thus enabling the realization of the loophole-free violation of a Bell inequality. This, along with a high-voltage, high-repetition-rate Pockels cell modulation set-up, allows us to accumulate sufficient data in the experimental time to extract genuine quantum randomness that is secure against the most general adversaries. By applying a large (137.90 gigabits × 62.469 megabits) Toeplitz-matrix hashing technique, we obtain 6.2469 × 107 quantum-certified random bits in 96 hours with a total failure probability (of producing a random number that is not guaranteed to be perfectly secure) of less than 10-5. Our demonstration is a crucial step towards transforming DIQRNG from a concept to a key aspect of practical applications that require high levels of security and thus genuine randomness7. Our work may also help to improve our understanding of the origin of randomness from a fundamental perspective.

Developing LC-MS/MS methods to quantify rivaroxabanin human plasma and urine: Application to therapeutic drug monitoring.

Rivaroxaban is an oral anticoagulant directly inhibiting the activity of Factor Xa, which is widely used for the prophylaxis of thromboembolic disorders. Therapeutic drug monitoring (TDM) is required during therapy for individual dosage adjustment. This study aimed at developing a liquid chromatography/tandem mass spectrometry method that was suitable for rivaroxaban TDM in human plasma and urine and exploring the feasibility of urine drug monitoring in medical care. A 3 min run time of the LC-MS/MS methods was established by employing an Acquity UPLC BEH C18 (2.1 × 50 mm, 1.7 µm) column using gradient elution of 10 mmol/L ammonium acetate containing 0.1% formic acid-0.1% formic acid acetonitrile as a mobile phase at a flow rate of 0.4 ml/min with calibration ranges of 0.5-400 and 10-10,000 ng/ml for human plasma and urine, respectively. Rivaroxaban was detected on a triple quadrupole tandem mass spectrometer with an electrospray ionization source in positive ion mode. The methods showed good linearity within the calibration range. The precision and accuracy, matrix effect, extraction recovery and stability in both human matrices were all validated and meet the international guideline requirements. These validated methods were successfully applied to support the TDM of an aged patient receiving rivaroxaban for therapy.

Experimental Realization of Device-Independent Quantum Randomness Expansion.

Randomness expansion where one generates a longer sequence of random numbers from a short one is viable in quantum mechanics but not allowed classically. Device-independent quantum randomness expansion provides a randomness resource of the highest security level. Here, we report the first experimental realization of device-independent quantum randomness expansion secure against quantum side information established through quantum probability estimation. We generate 5.47×10^{8} quantum-proof random bits while consuming 4.39×10^{8} bits of entropy, expanding our store of randomness by 1.08×10^{8} bits at a latency of about 13.1 h, with a total soundness error 4.6×10^{-10}. Device-independent quantum randomness expansion not only enriches our understanding of randomness but also sets a solid base to bring quantum-certifiable random bits into realistic applications.

Experimental Low-Latency Device-Independent Quantum Randomness.

Applications of randomness such as private key generation and public randomness beacons require small blocks of certified random bits on demand. Device-independent quantum random number generators can produce such random bits, but existing quantum-proof protocols and loophole-free implementations suffer from high latency, requiring many hours to produce any random bits. We demonstrate device-independent quantum randomness generation from a loophole-free Bell test with a more efficient quantum-proof protocol, obtaining multiple blocks of 512 random bits with an average experiment time of less than 5 min per block and with a certified error bounded by 2^{-64}≈5.42×10^{-20}.

Development of an LC-MS/MS method for quantifying two main metabolites of abivertinib in human plasma.

Abivertinib represents a highly selective irreversible epidermal growth factor receptor tyrosine kinase inhibitor. Two major metabolites of abivertinib, M7 and MII-6, were detected in human plasma, which are recommended to be monitored for safety reasons in clinical trial. A high-throughput quantification method utilizing liquid chromatography-tandem mass spectrometry was designed and verified to quantify abivertinib's primary metabolites in human plasma. Solid-phase extraction was used to process the plasma, and then the analytes underwent a gradient elution separation in an Aquity UPLC BEH C18 column (1.7 µm, 2.1 × 50 mm) with mobile phase A (10 mm ammonium acetate containing 0.1% formic acid) and mobile phase B (methanol-acetonitrile, 2:8, v/v, with 0.1% formic acid). Ion transitions of M7 (m/z 490.2 → 405.1) and MII-6 (m/z 476.2 → 391.1) were monitored under multiple reaction monitoring mode and electrospray ionization in positive ion mode. This simultaneous determination method was found to have acceptable precision, accuracy and linearity in the 0.5-500 ng/mL range for M7 and the 0.5-500 ng/mL range for MII-6, accompanied by a mild matrix effect but high recovery. Further stability assessments indicated that both analytes remained stable throughout the entire experimental process from harvesting whole blood to plasma extraction and analysis.

Performance of Test Supermartingale Confidence Intervals for the Success Probability of Bernoulli Trials.

Given a composite null hypothesis ℋ0, test supermartingales are non-negative supermartingales with respect to ℋ0 with an initial value of 1. Large values of test supermartingales provide evidence against ℋ0. As a result, test supermartingales are an effective tool for rejecting ℋ0, particularly when the p-values obtained are very small and serve as certificates against the null hypothesis. Examples include the rejection of local realism as an explanation of Bell test experiments in the foundations of physics and the certification of entanglement in quantum information science. Test supermartingales have the advantage of being adaptable during an experiment and allowing for arbitrary stopping rules. By inversion of acceptance regions, they can also be used to determine confidence sets. We used an example to compare the performance of test supermartingales for computing p-values and confidence intervals to Chernoff-Hoeffding bounds and the "exact" p-value. The example is the problem of inferring the probability of success in a sequence of Bernoulli trials. There is a cost in using a technique that has no restriction on stopping rules, and, for a particular test supermartingale, our study quantifies this cost.

Bounding the Plausibility of Physical Theories in a Device-Independent Setting via Hypothesis Testing.

The device-independent approach to physics is one where conclusions about physical systems (and hence of Nature) are drawn directly and solely from the observed correlations between measurement outcomes. This operational approach to physics arose as a byproduct of Bell's seminal work to distinguish, via a Bell test, quantum correlations from the set of correlations allowed by local-hidden-variable theories. In practice, since one can only perform a finite number of experimental trials, deciding whether an empirical observation is compatible with some class of physical theories will have to be carried out via the task of hypothesis testing. In this paper, we show that the prediction-based-ratio method-initially developed for performing a hypothesis test of local-hidden-variable theories-can equally well be applied to test many other classes of physical theories, such as those constrained only by the nonsignaling principle, and those that are constrained to produce any of the outer approximation to the quantum set of correlations due to Navascués-Pironio-Acín. We numerically simulate Bell tests using hypothetical nonlocal sources of correlations to illustrate the applicability of the method in both the independent and identically distributed (i.i.d.) scenario and the non-i.i.d. scenario. As a further application, we demonstrate how this method allows us to unveil an apparent violation of the nonsignaling conditions in certain experimental data collected in a Bell test. This, in turn, highlights the importance of the randomization of measurement settings, as well as a consistency check of the nonsignaling conditions in a Bell test.

Test of Local Realism into the Past without Detection and Locality Loopholes.

Inspired by the recent remarkable progress in the experimental test of local realism, we report here such a test that achieves an efficiency greater than (78%)^{2} for entangled photon pairs separated by 183 m. Further utilizing the randomness in cosmic photons from pairs of stars on the opposite sides of the sky for the measurement setting choices, we not only close the locality and detection loopholes simultaneously, but also test the null hypothesis against local hidden variable mechanisms for events that took place 11 years ago (13 orders of magnitude longer than previous experiments). After considering the bias in measurement setting choices, we obtain an upper bound on the p value of 7.87×10^{-4}, which clearly indicates the rejection with high confidence of potential local hidden variable models. One may further push the time constraint on local hidden variable mechanisms deep into the cosmic history by taking advantage of the randomness in photon emissions from quasars with large aperture telescopes.

Development and validation of a UPLC-MS/MS method for quantification of osimertinib (AZD9291) and its metabolite AZ5104 in human plasma.

Osimertinib (AZD9291) is a highly selective irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) designed to treat nonsmall-cell lung cancer patients with EGFR active and T790 M resistant mutations. A rapid and sensitive method for quantitative analysis by ultra-performance liquid chromatography-tandem mass spectrometry of osimertinib and its metabolite AZ5104 in human plasma was developed and validated. The samples were prepared by protein precipitation and separated on a BEH C18 column (2.1 × 50 mm, 1.7 µm) by gradient elution with 0.1% (v/v) formic acid and 10 mm ammonium acetate in water and acetonitrile as the mobile phase. Electrospray ionization in positive ion mode and multiple reaction monitoring were used to monitor the ion transitions at m/z 500.4 → 385.3 and 486.3 → 371.1. The results indicated that the method had excellent sensitivity and specificity. The validation was performed in a range from 0.5 to 100 ng/mL. Intra-day and inter-day precisions (in terms of RSD) were all <15%, and the accuracies (in terms of RE) were within ±15%. The lower limit of quantification, matrix effect, extraction recovery, stability and dilution integrity were also validated and satisfied the validation criteria. Finally, this method was successfully applied in a retrospective analysis, and the predose samples of 52 nonsmall-cell lung cancer patients who were enrolled in a novel third EGFR TKI clinical trial were analyzed for screening regardless of whether they had previously received osimertinib treatments.

Strong Loophole-Free Test of Local Realism.

We present a loophole-free violation of local realism using entangled photon pairs. We ensure that all relevant events in our Bell test are spacelike separated by placing the parties far enough apart and by using fast random number generators and high-speed polarization measurements. A high-quality polarization-entangled source of photons, combined with high-efficiency, low-noise, single-photon detectors, allows us to make measurements without requiring any fair-sampling assumptions. Using a hypothesis test, we compute p values as small as 5.9×10^{-9} for our Bell violation while maintaining the spacelike separation of our events. We estimate the degree to which a local realistic system could predict our measurement choices. Accounting for this predictability, our smallest adjusted p value is 2.3×10^{-7}. We therefore reject the hypothesis that local realism governs our experiment.

Development of a rapid and sensitive UPLC-MS/MS assay for simultaneous quantitation of Vorolanib and its metabolite in human plasma and application to a pharmacokinetics study.

Vorolanib is an oral tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). A sensitive and specific LC-MS/MS assay was developed and fully validated for simultaneous quantification of vorolanib and its main metabolite X297 in human plasma. The two analytes were extracted from K2-EDTA plasma samples by protein precipitation (PP) with acetonitrile, and chromatographically separated on a C18 reverse-phase column using a gradient elution. A SCIEX 5500 QTRAP® mass spectrometer system was operated in multiple-reaction monitoring mode (MRM) and all components were detected using positive electrospray ionization (ESI). The results successfully demonstrated that the method had satisfactory linearity, sensitivity, and selectivity in the concentration ranges of vorolanib (1.00-1000 ng/mL) and X297 (0.500-500 ng/mL). In this study, two concentration related peaks in the vorolanib and X297 detection channels were observed, which were speculated to be isomers of vorolanib and X297. In order to standardize the sample pretreatment process, the effect of lamp light and pH on the isomer reconversion was evaluated. The results indicated, that the exposure of samples to lamp light during the handling procedures, did not cause the conversion of the isomers. For the first time a robust and specific ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay for the high-throughput quantification of vorolanib and X297 in human plasma was established and validated following bioanalytical validation guidelines. The proposed method was successfully applied to clinical trials evaluating the pharmacokinetics of vorolanib tablets in Chinese advanced solid tumor patients.

Simultaneous determination of indapamide, perindopril and its active metabolite perindoprilat in human plasma using UPLC-MS/MS method.

Lots of studies showed the combination therapy of perindopril, indapamide and amlodipine could increase BP lowering efficacy and the benefits of high-risk patients. To evaluate potential pharmacokinetic interaction, a simultaneous UPLC-MS/MS quantification method of perindopril, perindoprilat and indapamide in human plasma was developed and validated. The plasma samples were prepared by solid phase extraction, and then separated on an X-terra MS C18 (2.1 mm × 150 mm, 3.5 µm) with isocratic elution. The ion transitions at m/z 369.165 â†’ 172.000 (perindopril), m/z 341.146 â†’ 170.112 (perindoprilat), m/z 366.010 â†’ 132.100 (indapamide), m/z 389.120 â†’ 206.200 (S10211-1, IS1) and m/z 394.080 â†’ 160.200 (S1641, IS2) were monitored under the positive ion mode of electrospray ionization with multiple reaction monitoring. This method exhibited great sensitivity, linearity, accuracy, and precision for the determination of perindopril, perindoprilat and indapamide over the range of 0.250-50.0 ng/mL. The average extraction recovery of perindopril, perindoprilat and indapamide samples at low, medium, and high concentration levels were between 85.9% and 93.6%, respectively. The stability of analytes over different storage and processing conditions in the whole study was also validated. The method is fast, accurate, sensitive and reproducible, which is suitable for the detection of the concentration of perindopril, perindoprilat and indapamide in human plasma.

A simple low-latency real-time certifiable quantum random number generator.

Quantum random numbers distinguish themselves from others by their intrinsic unpredictability arising from the principles of quantum mechanics. As such they are extremely useful in many scientific and real-world applications with considerable efforts going into their realizations. Most demonstrations focus on high asymptotic generation rates. For this goal, a large number of repeated trials are required to accumulate a significant store of certifiable randomness, resulting in a high latency between the initial request and the delivery of the requested random bits. Here we demonstrate low-latency real-time certifiable randomness generation from measurements on photonic time-bin states. For this, we develop methods to certify randomness taking into account adversarial imperfections in both the state preparation and the measurement apparatus. Every 0.12 s we generate a block of 8192 random bits which are certifiable against all quantum adversaries with an error bounded by 2-64. Our quantum random number generator is thus well suited for realizing a continuously-operating, high-security and high-speed quantum randomness beacon.

Efficient Randomness Certification by Quantum Probability Estimation.

For practical applications of quantum randomness generation, it is important to certify and further produce a fixed block of fresh random bits with as few trials as possible. Consequently, protocols with high finite-data efficiency are preferred. To yield such protocols with respect to quantum side information, we develop quantum probability estimation. Our approach is applicable to device-independent as well as device-dependent scenarios, and it generalizes techniques from previous works [Miller and Shi, SIAM Journal on Computing 46, 1304 (2017); Arnon-Friedman et al., Nature Communications 9, 459 (2018)]. Quantum probability estimation can adapt to changing experimental conditions, allows stopping the experiment as soon as the prespecified randomness goal is achieved, and can tolerate imperfect knowledge of the input distribution. Moreover, the randomness rate achieved at constant error is asymptotically optimal. For the device-independent scenario, our approach certifies the amount of randomness available in experimental results without first searching for relations between randomness and violations of fixed Bell inequalities. We implement quantum probability estimation for device-independent randomness generation in the CHSH Bell-test configuration, and we show significant improvements in finite-data efficiency, particularly at small Bell violations which are typical in current photonic loophole-free Bell tests.

Determination of BPI15086 and its metabolite in human plasma by ultra-high performance liquid chromatography-MS/MS and its application to a pharmacokinetic study.

Aim: BPI15086 is a potent, irreversible mutant-selective inhibitor of both EGFR (EGFR tyrosine kinase inhibitor) and the T790M resistance mutations tyrosine kinase. A simultaneous quantification method of BPI15086 and its main metabolite in human plasma using LC-MS/MS is documented and fully validated in this study. Methodology & results: Plasma samples were extracted and chromatographed on an Acquity ultra-high performance liquid chromatography BEH C18 column with a gradient elution. Detection was performed on a Sciex 5500 QTRAP® mass spectrometer using positive electrospray ionization. The results indicated that the method had excellent sensitivity and specificity. Conclusion: For the first time a sensitive and robust ultra-high performance liquid chromatography-MS/MS method was established and validated of BPI15086 in human plasma, this method was successfully applied in a first-in-human Phase I clinical trial studying the pharmacokinetics of the BPI15086 tablet in Chinese non-small-cell lung cancer patients.

Certifying Quantum Randomness by Probability Estimation.

We introduce probability estimation, a broadly applicable framework to certify randomness in a finite sequence of measurement results without assuming that these results are independent and identically distributed. Probability estimation can take advantage of verifiable physical constraints, and the certification is with respect to classical side information. Examples include randomness from single-photon measurements and device-independent randomness from Bell tests. Advantages of probability estimation include adaptability to changing experimental conditions, unproblematic early stopping when goals are achieved, optimal randomness rates, applicability to Bell tests with small violations, and unsurpassed finite-data efficiency. We greatly reduce latencies for producing random bits and formulate an associated rate-tradeoff problem of independent interest. We also show that the latency is determined by an information-theoretic measure of nonlocality rather than the Bell violation.